DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after Aug 29th, 2023, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on Aug 29th, 2023. Claims 1-20 are currently pending.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/402,304, fails to provide adequate support or enablement for subject matter in the manner required by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Accordingly, claims 1-20 are not entitled to the benefit of the filing date of the prior application. The reasoning for denying the priority is described in the 35 U.S.C. 112(a) claim analysis section below.
Specification
The abstract of the disclosure is objected to because there is no description of subject matters in the specification. Specifically, “mucolytic and/or DNA disrupting agents”, “complement receptors C3R and/or C5R together with TNF-receptor, IL-6 receptor and/or TLR4 and TLR9”, and “nanostilbene” are compositions never mentioned in the specification or the claims as written. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112 – Written Description
6. The following is a quotation of the first paragraph of 35 U.S.C. §112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. §112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), the first paragraph, for failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USP USPQ2d at 1406.
Independent claim 1 directs to a method of treating acute respiratory distress syndrome (ARDS). The phrase “a composition capable of inducing the process of RNA interference to one or more inflammatory mediators” refers to a broad genus of compositions not defined by structure but by the function: “capable of inducing the process of RNA interference…”. The genus encompasses numerous species of therapeutics, such as small molecules and nucleic acid-based reagents under the broadest reasonable interpretation of the functional limitation. An original research article by Shan et al., published before the effective filing date of the instant application, teaches that small molecules can enhance the RNAi pathway (Shan G, et al. A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol. 2008 Aug;26(8):933-40. doi: 10.1038/nbt.1481. Epub 2008 Jul 20.). In addition, to overcome the major clinical barriers for effective RNAi therapies, tissue specificity, degradation, and delivery efficiency, a review of the state of the art for RNAi therapeutics by Hu et al teaches that conjugation with proteins (e.g. antibodies), lipids (encapsulation with lipid nanoparticles), or sugar (e.g. GalNAc) are in rapid development to enable clinical translation of efficacious RNAi-based targeted therapies (Hu B. et al., Therapeutic siRNA: state of the art. Signal Transduct Target Ther. 2020 Jun 19;5,1:101). These developments further broaden the scope of “a composition capable of inducing the process of RNA interference to…”, requiring reasonable representative working examples in the specification in order for one skilled in the art to conclude that the applicant are in possession of the claimed inventions at the time of filing.
Moreover, “one or more inflammatory mediators” covers an enormous number of combinations of multiple therapeutic targets, each with distinct signaling pathways and functional partners, further enhancing the unpredictability of the claimed inventions.
Aside from the high degree of unpredictability across different types of molecules that are “capable of inducing the process of RNA interference”, a high degree of variation is observed with respect to the diverse theoretical embodiments within the nucleic acid-based compositions capable of inducing the process of RNAi as disclosed in the specification based on the current state of the art reviewed by Winkle et al. (Winkle M et al. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov. 2021 Aug;20, 8:629-651), published before the effective filing date of the instant application, and in view of a more recent review by Corydon, Ida Juhl et al. (25 years of maturation: A systematic review of RNAi in the clinic. Molecular Therapy Nucleic Acids, 2023 Jul 18;33:469-482). Winkle et al. and Corydon et al. both teach that barriers of specificity and delivery underlie the high levels of unpredictability for the broad genus of reagents that are capable of knocking down target expression. And yet, the only example in the specification (pages 19, ¶[0088] – [0092]) was not shown to induce “the process of RNA interference” to the preferred embodiment of therapeutic target complement component 5 (C5) in the pulmonary tissue of the animal model of ARDS. Other than detailed descriptions of the various configurations of nucleic acid-based RNAi reagents that are gleaned from public literature and a survival profile of basic mouse model experiment, there is currently no working example in the specification demonstrating the feasibility of using said reagents to knock down C5 expression in the pulmonary tissue of “patient suffering from ARDS”. There is no direct evidence that a “RNA interference process to” C5 was in fact induced in the pulmonary tissue of experimental mice, nor is there evidence that such down-regulation of C5 expression contributed to the reversal of ARDS symptoms and pathology in these experimental mice.
Claim 1 refers to the therapeutic target as “one or more inflammatory mediators”. In view of page 1 of specification, ¶[0002] Field of the Invention, “more specifically the invention pertains to treatment of acute lung injury through selective gene silencing of inflammatory mediators”. Since there is an absence of special definitions in the instant application, Collins teaches that “Inflammatory mediator” is any molecule that is released by cells in response to injury or infection and plays a role in regulating the immune response (Collins English Dictionary Online Edition; screenshot of the definition page for “inflammatory mediator” provided as NPL). This definition is widely accepted by ordinarily skilled artisans. Weissmann confirms that “cellular release” and “fluid activation” phases are common traits of mediators of inflammation (Weissman G. Mediators of Inflammation. 1974, Plenum Press, ISBN: 0-306-30815-0, relevant pages from the Library of Congress Cataloging of Publication Data). Both old scientific doctrines, such as Stoughton (Stoughton RB. Mediators of inflammation. Arch Dermatol. 1966 May;93, 5:601-7), and more recent reviews, such as White (White M. Mediators of inflammation and the inflammatory process. J Allergy Clin Immunol. 1999 Mar;103: S378-81), teach that membrane-bound receptors for inflammatory mediators are not mediators themselves despite contributing to the inflammation development. In addition, diverse molecule types have been recognized as inflammatory mediators, including small molecules (e.g. histamine, serotonin etc.), lipids (e.g. prostaglandins, leukotrienes etc.), and gases (e.g. nitric oxide, carbon monoxide, etc.), none of which are suitable direct targets of RNAi or gene silencing as these are not proteins encoded by genes.
On page 4-5, ¶[0025]-[0044] list 20 embodiments of the preferred targets of RNAi, including receptors for inflammatory mediators, transcription factors, or intracellular signaling molecules that do not get released from cells in response to inflammatory stimuli. In another word, none of these 20 embodiments support the claimed inventions that target “one or more inflammatory mediators”, yet the applicant seems to have expanded the “inflammatory mediators” arbitrarily to any protein-based molecules that interact with any well accepted inflammatory mediators, or any molecule that is involved in the inflammation or anti-inflammation signaling cascades, regardless of whether the molecule is released from cells into circulation for distal impact or remains intracellular.
The single working example provided by the applicant in specification on page 19, ¶[0088]-[0092], describes the effect of a preferred embodiment for inducing gene silencing to C5, an anaphylatoxin with structure distinct from the other diverse species of therapeutic targets within the broad genus in claim 1, thereby is inadequate to represent the entire genus of therapeutics with highly unpredictable outcomes.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 1 is overly broad with insufficient evidence of possession at the time of filing to an ordinarily skilled artisan. Therefore, claim 1 does not meet the written description requirement. Claims 2-20 are rejected for both depending from a rejected claim and for not being limited to an embodiment that is adequately described. They are claims that are still directed to a broad genus that is not adequately described for the same reasons as discussed above in the rejection.
Claim Rejections - 35 USC § 112 - Enablement
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
The claimed invention directs to an in vivo method of treating ARDS in a patient through steps that involve obtaining patient suffering from ARDS, and a combination of administering a composition capable of inducing the process of RNAi to one or more inflammatory mediators and providing a regenerative population of cells for preventing long-term effects of ARDS. Thus, the methods require a reliable implementation of: i) preventing, inhibiting or reversing inflammatory mediator(s) expression in in the patient; ii) evaluating the efficacy of required amount of the reagent and the impact on the pathology underlying ARDS; in iii) any patient.
The Breadth of the Claims
The scope of the independent claim 1 encompasses any modulating reagent under any reaction conditions to prevent, inhibit or reverse a pathogenic level of inflammatory mediator(s) gene expression in any patient suffering from ARDS, which, as a clinical manifestation of defined symptoms and underlying pathologies, has diverse etiologies that range from infection to injury. Claims 2-20 further limit the breadth of claim 1, but still frame the selection of reagents to a substantially broad group of species without further limiting on the selection of therapeutic targets that could contribute to the alleviation of ARDS-related symptoms or reversing the underlying pathophysiology in a patient. While the specification made lengthy descriptive disclosures of limited species of the broad genus, no working example was offered to support the breadth of the claims with definitive evidence at the tissue level, the cellular level, the molecular level, or the pulmonary functional level for either “treating ARDS” or “inducing the process of RNAi to one or more inflammatory mediators” beyond mere tallying of survived mice by day 4 post treatment. No working example was provided to support the “providing a regenerative cell population to prevent long term effects of said ARDS” either. Accordingly, claim 1 is unduly broad.
Guidance of the Specification
As analyzed above in 35 U.S.C. §112(a) written description, the specification includes only generic information gleaned from publicly available information in addition to inconsistencies in Example 1: on page 18-19 ¶[0088]-[0092], in that the specification is unclear over which molecular target is used as an working example: the inflammatory mediator C5, or C5aR the receptor for C5a, a cleaved and activated fragment of C5. In ¶[0088] and [0091], C5aR siRNA is referenced. In ¶[0089] and [0092], C5 siRNA is referenced. However, the siRNA sequences provided in ¶[0089], SEQ ID NO: 1 is near identical with only 2 extra adenosine residues (AA) on the 3’ end when compared with the C5aR siRNA sequences #1 used by Zheng et al., and SEQ ID NO: 2 is identical with siRNA sequence #2 published in Zheng et al. (Zheng X. et al., Gene silencing of complement C5a receptor using siRNA for preventing ischemia/reperfusion injury. Am J Pathol. 2008 Oct;173(4):973-80. Epub 2008 Sep 4.; page 974, left column, second ¶) published ahead of the effective filing date of the instant application. See the comparisons below:
C5aR siRNA #1 Zheng 2008 (top) vs. SEQ ID NO:1, Instant application (bottom):
5′-GATCCCGTTTAGAGTGAGCAGAGGCAACTTCAAGAGAGTTGCCTCTGCTCACTCTAAATTTTTTCCA-3′
5′-GATCCCGTTTAGAGTGAGCAGAGGCAACTTCAAGAGAGTTGCCTCTGCTCACTCTAAATTTTTTCCAAA-3′
C5aR siRNA #2: Zheng 2008 (top) vs. SEQ ID NO:2, Instant application (bottom):
5′-AGCTTTTGGAAAAAATTTAGAGTGAGCAGAGGCAACTCTCTTGAAGTTGCCTCTGCTCACTCTAAACGG-3′
5′-AGCTTTTGGAAAAAATTTAGAGTGAGCAGAGGCAACTCTCTTGAAGTTGCCTCTGCTCACTCTAAACGG-3′
In ¶[0091], the applicant describes the use of pRNAT-U6.1/Neo siRNA expression vector, a mammalian expression plasmid used primarily for in vitro experiments because the inclusion of a GFP fluorescent protein reporter to visualize transfection efficiency. GFP is a known antigenic foreign protein as it derives from algae. Using expression vectors to deliver GFP expression in vivo renders the survival data provided in the example questionable at best as unpredictable immunogenicity was introduced.
The confusion over the exact target of the siRNA sequences raises concern over the reliability of the in vivo example and the mouse survival data. The absence of any actual experimental data at the tissue, cellular, molecular, or pulmonary function levels in the instant application suggests that no animal experiment was actually performed. Since the specification is silent on important details as to the strain of the mice chosen or the statistical basis for the experimental design, the examiner does not interpret this example as an enabling disclosure for the claimed invention.
More importantly, the provided example used siRNA sequences against C5aR, a receptor for C5, instead of the claimed inflammatory mediator(s) as target(s). To one skilled in the art, these are not seen as working examples of treating ARDS, but rather hypothetical experimental steps toward a proof-of-concept study for the claimed inventions. There is no recitation of evidence for successful inhibition, reversal, or alleviation of C5 expression in an in vivo model of ARDS.
The State of the Prior Art
With regard to the state of the art, there is growing concern over the inadequate animal models widely used in literature to emulate the clinical observations of ARDS in the human patient population. A 2017 Grover Conference Series review article by Uhlig et al. summarized the ongoing challenges to model ARDS using small animal models, and highlighted the reasons that invalidate research findings based on inadequate modeling using small animals, particularly inbred, untrained, immunity naïve mice to model ARDS. The difficulties and suggested improvements are listed in Table 1, (attached below). This update paints a challenging picture to use small animal models as credible working examples.
Uhlig et al. teaches that the preferable predictive endpoints in any model of ARDS remain unclear. At present, the best recommendation is to use endpoints that can be compared across studies (i.e. PaO2/FiO2 ratio, compliance, wet-to-dry weight ratio) rather than percentage data. Another important and often overlooked issue pointed out by Uhlig et al. is the fact that the thermoneutral environmental temperatures for mice and rats are 30 °C and 28 °C, respectively; thus, at room temperature (20–22 °C) they suffer from cold stress with the associated significant metabolic changes. Uhlig et al. suggests that clinically relevant models of ARDS will have to closer recapitulate important properties of the disease while taking into account species-specific confounders.
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The Level of Predictability in the Art
Given the recent success in RNAi therapeutics in the clinical stage, it is encouraging to explore novel RNAi-based solutions to difficult to treat clinical conditions in patients. However, numerous challenges for elevating animal model experimental data to the clinical phases of investigation is observed prominently in recent years, highlighting the highly unpredictability in the art.
The state of the art requires experimentation including analysis of a representative amount of effective reagent and environmental conditions in order to treat ARDS in a patient. Therefore, the methods to be followed to achieve the limitations of the instant claims are highly unpredictable. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species whether other species will work. The diverse compositions capable of inducing the process of RNAi, the variable structures of the potential therapeutic compositions that may encompass protein, lipid, and sugar conjugated short/small interference RNAs, and the unpredictable behaviors of combinatorial targeting of one or more inflammatory mediators render it imperative to have sufficient number of representative working models to enable one with ordinary skills in the art to follow the examples in order to make and use the claimed inventions with reasonable expectation for success.
The Quantity of Experimentation necessarily Needed
In light of the high level of unpredictability in the art, and the limited amount of direction provided by the inventor, and the noticeable absence of meaningful working examples critiqued above, the quantity of experimentation necessarily needed to make or use the invention, especially with respect to alleviate or reverse the symptoms of ARDS through suppression of gene expression of a wide gamut of inflammatory mediators based on the disclosure is considerably high. For example, it would be necessary for one skilled in the art to identify optimal inflammatory mediator targets, siRNA sequence and composition modifications, dosing schemes, administration routes, and timepoints to make or use the invention to treat clinical indications of ARDS in a clinically relevant large animal model. There would be an unreasonable amount of experimentation required by a person of ordinary skill in the art.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the specification and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636